tetano
Editor, Senior Moderator
J Biol Chem
. 2024 Oct 7:107871.
doi: 10.1016/j.jbc.2024.107871. Online ahead of print. Cellular NS1-BP Protein Interacts with the mRNA Export Receptor NXF1 to Mediate Nuclear Export of Influenza Virus M mRNAs
Ke Zhang[SUP] 1 [/SUP], Tolga Cagatay[SUP] 2 [/SUP], Dongqi Xie[SUP] 2 [/SUP], Alexia E Angelos[SUP] 3 [/SUP], Serena Cornelius[SUP] 2 [/SUP], Vasilisa Aksenova[SUP] 4 [/SUP], Sadaf Aslam[SUP] 5 [/SUP], Zhiyu He[SUP] 6 [/SUP], Matthew Esparza[SUP] 2 [/SUP], Ashley Vazhavilla[SUP] 2 [/SUP], Mary Dasso[SUP] 4 [/SUP], Adolfo García-Sastre[SUP] 7 [/SUP], Yi Ren[SUP] 3 [/SUP], Beatriz M A Fontoura[SUP] 8 [/SUP]
Affiliations
Influenza A viruses have eight genomic RNAs that are transcribed in the host cell nucleus. Two of the viral mRNAs undergo alternative splicing. The M1 mRNA encodes the matrix protein 1 (M1) and is also spliced into M2 mRNA, which encodes the proton channel matrix protein 2 (M2). Our previous studies have shown that the cellular NS1-binding protein (NS1-BP) interacts with the viral non-structural protein 1 (NS1) and M1 mRNA to promote M1 to M2 splicing. Another pool of NS1 protein binds the mRNA export receptor NXF1 (nuclear RNA export factor-1), leading to nuclear retention of cellular mRNAs. Here we show a series of biochemical and cell biological findings that suggest a model for nuclear export of M1 and M2 mRNAs despite the mRNA nuclear export inhibition imposed by the viral NS1 protein. NS1-BP competes with NS1 for NXF1 binding, allowing the recruitment of NXF1 to the M mRNAs after splicing. NXF1 then binds GANP (Germinal-center Associated Nuclear Protein), a member of the TRanscription and EXport complex (TREX)-2. Although both NS1 and NS1-BP remain in complex with GANP-NXF1, they dissociate once this complex docks at the nuclear pore complex (NPC), and the M mRNAs are translocated to the cytoplasm. Since this mRNA nuclear export pathway is key for expression of M1 and M2 proteins that function in viral intracellular trafficking and budding, these viral-host interactions are critical for influenza virus replication.
Keywords: GANP (Germinal-center Associated Nuclear Protein); M1 (matrix protein 1 of influenza virus); NS1 (non-structural protein 1 of influenza A virus); NS1-BP (cellular NS1-Binding Protein); NXF1 (nuclear RNA export factor-1); NXT1 (nuclear transport factor 2 like export factor 1); TREX-2 (TRanscription and EXport complex -2); influenza virus; mRNA export.
. 2024 Oct 7:107871.
doi: 10.1016/j.jbc.2024.107871. Online ahead of print. Cellular NS1-BP Protein Interacts with the mRNA Export Receptor NXF1 to Mediate Nuclear Export of Influenza Virus M mRNAs
Ke Zhang[SUP] 1 [/SUP], Tolga Cagatay[SUP] 2 [/SUP], Dongqi Xie[SUP] 2 [/SUP], Alexia E Angelos[SUP] 3 [/SUP], Serena Cornelius[SUP] 2 [/SUP], Vasilisa Aksenova[SUP] 4 [/SUP], Sadaf Aslam[SUP] 5 [/SUP], Zhiyu He[SUP] 6 [/SUP], Matthew Esparza[SUP] 2 [/SUP], Ashley Vazhavilla[SUP] 2 [/SUP], Mary Dasso[SUP] 4 [/SUP], Adolfo García-Sastre[SUP] 7 [/SUP], Yi Ren[SUP] 3 [/SUP], Beatriz M A Fontoura[SUP] 8 [/SUP]
Affiliations
- PMID: 39384042
- DOI: 10.1016/j.jbc.2024.107871
Influenza A viruses have eight genomic RNAs that are transcribed in the host cell nucleus. Two of the viral mRNAs undergo alternative splicing. The M1 mRNA encodes the matrix protein 1 (M1) and is also spliced into M2 mRNA, which encodes the proton channel matrix protein 2 (M2). Our previous studies have shown that the cellular NS1-binding protein (NS1-BP) interacts with the viral non-structural protein 1 (NS1) and M1 mRNA to promote M1 to M2 splicing. Another pool of NS1 protein binds the mRNA export receptor NXF1 (nuclear RNA export factor-1), leading to nuclear retention of cellular mRNAs. Here we show a series of biochemical and cell biological findings that suggest a model for nuclear export of M1 and M2 mRNAs despite the mRNA nuclear export inhibition imposed by the viral NS1 protein. NS1-BP competes with NS1 for NXF1 binding, allowing the recruitment of NXF1 to the M mRNAs after splicing. NXF1 then binds GANP (Germinal-center Associated Nuclear Protein), a member of the TRanscription and EXport complex (TREX)-2. Although both NS1 and NS1-BP remain in complex with GANP-NXF1, they dissociate once this complex docks at the nuclear pore complex (NPC), and the M mRNAs are translocated to the cytoplasm. Since this mRNA nuclear export pathway is key for expression of M1 and M2 proteins that function in viral intracellular trafficking and budding, these viral-host interactions are critical for influenza virus replication.
Keywords: GANP (Germinal-center Associated Nuclear Protein); M1 (matrix protein 1 of influenza virus); NS1 (non-structural protein 1 of influenza A virus); NS1-BP (cellular NS1-Binding Protein); NXF1 (nuclear RNA export factor-1); NXT1 (nuclear transport factor 2 like export factor 1); TREX-2 (TRanscription and EXport complex -2); influenza virus; mRNA export.